The increased survival of premature infants in modern neonatal intensive care units has caused a resurgence of retinopathy of prematurity (ROP). It is reasoned that as more and smaller premature babies survive, the incidence of visual loss from ROP will continue to increase unless effective treatments are found. Four decades ago, a high correlation was found between inspired levels of oxygen by neonates and development of ROP. Yet, basic questions remain about the pathophysiology of the condition. It appears to involve two characteristic events: an attenuation of retinal blood vessels that occurs while a premature infant is undergoing oxygen therapy, and a proliferation of retinal blood vessels that is promoted by removal to room air breathing. The ultimate goal of this research is to fully characterize these two aspects of ROP and to begin to develop methods for their prevention based on understanding gained from studies of a rat model. To this end, four interrelated research projects are proposed: 1) an attempt to reduce retinal susceptibility to oxygen through antioxidant supplementation; 2) an attempt to reduce the propensity of the retina for abnormal vascular proliferation through supplementation with antiangiogenic factors; 3) an attempt to determine the role of ischemia-induced hypoxia in the vasoproliferative response; and 4) an attempt to describe in detail the normal retinal vasoformation process, with particular emphasis on the dynamics of spindle-cell differentiation. Criticism of animal models of ROP has focused on their inability to produce retinal detachment, the critical end-stage in infants. Our strategy for using rats in spite of this drawback is built upon the following premise: If a pharmacologic means of arresting the early manifestations of oxygen-induced retinopathy can be found for animals, it is possible that by applying the same agents, we will provide effective therapy to infants. The repression of these early events in neonates may eliminate retinal detachment by removing its stimulus.